Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease.
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Authors
Palmas, Maria Francesca
Ena, Anna
Burgaletto, Chiara
Casu, Maria Antonietta
Cantarella, Giuseppina
Carboni, Ezio
Etzi, Michela
De Simone, Alfonso
Fusco, Giuliana
Cardia, Maria Cristina
Lai, Francesco
Picci, Luca
Tweedie, David
Scerba, Michael T
Coroneo, Valentina
Bernardini, Renato
Greig, Nigel H
Pisanu, Augusta
Publication Date
2022-01Journal Title
Neurotherapeutics
ISSN
1933-7213
Publisher
Springer Science and Business Media LLC
Volume
19
Issue
1
Pages
305-324
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Palmas, M. F., Ena, A., Burgaletto, C., Casu, M. A., Cantarella, G., Carboni, E., Etzi, M., et al. (2022). Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease.. Neurotherapeutics, 19 (1), 305-324. https://doi.org/10.1007/s13311-022-01182-2
Abstract
Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.
Keywords
Alpha-synuclein, Cytokine, Drug repositioning, Immunomodulation, Motor impairment, Neuroprotection, Animals, Cytokines, Disease Models, Animal, Disease Progression, Drug Repositioning, Humans, Microglia, Neuroprotective Agents, Parkinson Disease, Rats, Substantia Nigra, Thalidomide, Tumor Necrosis Factor-alpha, alpha-Synuclein
Sponsorship
National Institute on Aging (Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, MD, United States)
University of Cagliari (Intramural Research Program at the University of Cagliari)
European Research Council (ERC CoG BioDisOrder 819644)
Identifiers
s13311-022-01182-2, 1182
External DOI: https://doi.org/10.1007/s13311-022-01182-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337467
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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